Direct conversion of lignin to functionalized diaryl ethers via oxidative cross-coupling

Efficient valorization of lignin, a sustainable source of functionalized aromatic products, would reduce dependence on fossil-derived feedstocks. Oxidative depolymerization is frequently applied to lignin to generate phenolic monomers. However, due to the instability of phenolic intermediates, repolymerization and dearylation reactions lead to low selectivity and product yields. Here, a highly efficient strategy to extract the aromatic monomers from lignin affording functionalized diaryl ethers using oxidative cross-coupling reactions is described, which overcomes the limitations of oxidative methods and affords high-value specialty chemicals. Reaction of phenylboronic acids with lignin converts the reactive phenolic intermediates into stable diaryl ether products in near-theoretical maximum yields (92% for beech lignin and 95% for poplar lignin based on the content of β−O−4 linkages). This strategy suppresses side reactions typically encountered in oxidative depolymerization reactions of lignin and provides a new approach for the direct transformation of lignin into valuable functionalized diaryl ethers, including key intermediates in pharmaceutical and natural product synthesis.

The authors proposed an effective procedure of lignin valorization consisting of two steps: oxidative coupling and methylation of the acid. The reaction conditions were optimized, including copper (II) source, base, ligand, solvent, catalyst loading, oxygen pressure, time, and temperature. As one of the most significant advances established by the authors, this protocol enables an efficient generation of various ethers from beech, poplar, and pine lignin in near-theoretical maximum yields with suppression of repolymerization and dearylation side reactions of the reactive phenol intermediates. The authors provided a detailed analysis of the HSQC spectra of the initial lignin polymer and final reaction mixtures. The authors found a correlation between the ratio of the linkages in lignin of three different types and the structures of the observed products. A scope of arylboronic acids with various substituents (EDG and EWG) was performed. Finally, several convincing mechanistic studies were elaborated: cleavage of C-C and C-O bonds and Cham-Lam coupling with simple substrates c-i, k under standard conditions. For the technical part, the supporting information includes the perfectly elaborated calculation of the ethers' yield based on starting lignin, as well as the linkages content calculation and calibration by the HSQC NMR spectroscopy technique. The spectral data corresponds to the proposed structures and is well-delivered. The citations are perfectly balanced.
Overall, I believe this impactful discovery dramatically pushed the boundaries of the lignin depolymerization topic. Undoubtedly, these advances in the direct conversion of lignin will interest a broad scientific audience. Thus, I fully support the publication of this manuscript in Nat. Commun. with minor revisions and four additional experiments outlined below. 1) Have you tried to subject lignocellulosic biomass, e.g., wood sawdust, directly to your reaction conditions? Is it possible to isolate any quantity of the pure desired product 1b from lignocellulose with the proposed method?
2) Does coupling of beech lignin with cyclohexylboronic acid (CAS 4441-56-9) result in product 1b under the established conditions? Although there is an entry with methylboronic acid 15a, a cyclic alkylboronic acid should be tested.
3) Can you recycle copper (II) heterogeneous catalyst and reuse it? How efficient will the recycled catalyst be for beech lignin valorization to produce 1b? 4) What is the product yield with 10 mol% amount of Cu(II) catalyst? 5) Although poplar lignin is a bit more efficient under your reaction conditions (95% yield of ethers, 71% of 1b), you performed a scope with beech lignin (92% yield of ethers, 68% of 1b). Is there any explanation for this choice? This is an interesting paper that describes an oxidative fragmentation of Lignin and a subsequent crosscoupling reaction of active phenolic intermediates with 4-chlorophenylboronic acid using Cu complex catalysts. Authors have already studied a series of Cu catalysts to synthesize methyl esters with Lignin as a source of "methylating reagents", in which CO was simultaneously formed as a co-product (Angew Chem. Int. Ed., 2022, 61, e202209093). This time authors found out the combination of Cu catalyst (Cupper triflate) and L1 (Bphen) ligand to be effective for the current reaction system. The high yields of diaryl ether products obtained in this reaction system are quite attractive, but novelty and significant advance of this work is weak in terms of "organic chemistry" and "catalytic chemistry".
Thank you for these positive remarks, indeed the focus of this work is on sustainable chemistry.
1. Lignin is recognized as a raw material to produce "bulk chemicals (aromatics, phenols, etc)". Authors had better rationalize the motivation and social impact to synthesize "specialty chemicals" using large amounts of stoichiometric reagents and excess 4-chlorophenylboronic acid.
We have expanded the introduction to better justify the approach used: Diaryl ethers are typically prepared from cross-coupling reactions between petrochemical-derived substrates, specifically, phenols with excess electrophiles, i.e. aryl halides, or nucleophiles, i.e. boronic acids. 34 Using lignin as a starting material to synthesize functionalized diaryl ether is advantageous as lignin is an abundant, inexpensive and renewable material. 1-6 The direct conversion of lignin to diaryl ethers in a single step process requires fewer reagents and solvents than a two-step process in which phenols are initially generated from lignin and then further transformed. 5,10,23 2. Introduction should contain comprehensive overview using homogeneous and heterogeneous catalysts in oxidative fragmentation of Lignin with literature survey. A table in the supporting information summarizing the results of previous papers will be helpful for readers to understand the background of this work.
We have expanded the discussion as requested and prepared and added a table to the SI: Many homogeneous and heterogeneous catalytic oxidative methods that cleave the C−C bonds of the alkyl side chains to depolymerize lignin have been reported, but typically they are limited by poor selectivity and consequently low product yields (Fig. 1). 12-23 The catalysts reported for the oxidative fragmentation of lignin are summarized in Table S1. 3. What is the reason to show high activity of Cu(OTf) 2 -L1 for this system, compared to others? What is the role of Cu(OTf) 2 and L1 ligand? What is the reason to suppress "side reactions"? Is it possible to explain side reactions to be suppressed with kinetics studies?
We added further text to explain the high activity of Cu(OTf) 2 -L1: Since the triflate anions in Cu(OTf) 2 are weakly coordinating and readily displaced, 35-36 Cu(OTf) 2 is expected to react with L1, a bidentate N-donor ligand, to form the active catalyst in situ. L1 is an electronrich ligand that increases the electron density on the Cu center, which facilitates oxidation Cu(II) to Cu(III), a key step in the reaction (i.e. the more electron rich the Cu center the easier it is to oxidize). 30,37 Further details to demonstrate the role of catalyst and ligand based on a series of additional control experiments are provided in the SI: The roles of Cu(OTf) 2 , L1 and K 2 CO 3 were investigated through a series of control experiments (Fig. S15). The Cu complex and base are indispensable for aerobic −OH group oxidation, C−C bond activation and Cham-Lam coupling. L1 coordinated to the Cu center to promote the Cham-Lam coupling of the boronic acid with the phenol intermediates. We have performed a kinetic study that helps to rationalize the suppression of side reactions: The kinetic study demonstrates that C−C bond activation to release reactive phenolic intermediates is slower than Cham-Lam coupling between phenol and boronic acid, which ensures rapid capture of the phenolic intermediates with boronic acid, preventing side reactions (Fig. S16). We performed recycling experiments and added the following discussion: A CuL1 complex is formed in situ (evidenced by mass spectrometry, Fig. S1), which serves as the actual catalyst, and is sufficiently stable to be isolated after reaction, recycled and reused with only a minor loss in activity (Fig. S1). The complex was isolated by removal of the solvent after reaction and extraction with CH 2 Cl 2 (5 mL) and H 2 O (5 mL). The organic phase was washed with H 2 O (3×5 mL) and concentrated under vacuum. The complex was purified by column chromatography (mobile phase: 10% methanol (volume ratio) in CH 2 Cl 2 ).
We also added TOFs to Fig. S1.

Reviewer #2 (Remarks to the Author):
The manuscript "Direct Conversion of Lignin to Functionalized Diaryl Ethers via Oxidative Cross-coupling" by Prof. Paul J. Dyson and Mingyang Liu describes a novel strategy of phenolic monomers' extraction from lignin. In this study, the authors applied oxidative copper-catalyzed cross-coupling reaction of beech lignin with phenylboronic acids affording functionalized diaryl ethers in a simple and highly efficient manner. The authors proposed an effective procedure of lignin valorization consisting of two steps: oxidative coupling and methylation of the acid. The reaction conditions were optimized, including copper (II) source, base, ligand, solvent, catalyst loading, oxygen pressure, time, and temperature. As one of the most significant advances established by the authors, this protocol enables an efficient generation of various ethers from beech, poplar, and pine lignin in near-theoretical maximum yields with suppression of repolymerization and dearylation side reactions of the reactive phenol intermediates. The authors provided a detailed analysis of the HSQC spectra of the initial lignin polymer and final reaction mixtures. The authors found a correlation between the ratio of the linkages in lignin of three different types and the structures of the observed products. A scope of arylboronic acids with various substituents (EDG and EWG) was performed. Finally, several convincing mechanistic studies were elaborated: cleavage of C-C and C-O bonds and Cham-Lam coupling with simple substrates c-i, k under standard conditions. For the technical part, the supporting information includes the perfectly elaborated calculation of the ethers' yield based on starting lignin, as well as the linkages content calculation and calibration by the HSQC NMR spectroscopy technique. The spectral data corresponds to the proposed structures and is well-delivered. The citations are perfectly balanced.
Overall, I believe this impactful discovery dramatically pushed the boundaries of the lignin depolymerization topic. Undoubtedly, these advances in the direct conversion of lignin will interest a broad scientific audience. Thus, I fully support the publication of this manuscript in Nat. Commun. with minor revisions and four additional experiments outlined below.
We thank you for the positive remarks.
1. Have you tried to subject lignocellulosic biomass, e.g., wood sawdust, directly to your reaction conditions? Is it possible to isolate any quantity of the pure desired product 1b from lignocellulose with the proposed method?
2. Does coupling of beech lignin with cyclohexylboronic acid (CAS 4441-56-9) result in product 1b under the established conditions? Although there is an entry with methylboronic acid 15a, a cyclic alkylboronic acid should be tested.
We evaluated cyclohexylboronic acid and added the data to Table 1 and commented on the result in the discussion: Alkyl boronic acids (15a, 16a) do not function as coupling reagents.